A lack of animal models is limiting progress in the field of migraine research. Calcitonin gene-related peptide (CGRP) plays a critical role in migraine, as evidenced by recent success of CGRP antagonists in clinical trials. In order to better understand the role of CGRP in migraine, we generated transgenic mice that overexpress human receptor activity-modifying protein 1 (hRAMP1), the rate limiting subunit of the CGRP receptor, in the nervous system (nestin/hRAMP1 mice). Using a light/dark box assay to assess light-aversion behavior, the nestin/hRAMP1 mice spend significantly less time in light following central injection of CGRP. We believe the light-aversion that these mice exhibit models photophobia, or exacerbation of head pain that is caused by light exposure as experienced by many migraineurs. Triggering light aversion in these mice by means of a more physiologically relevant manner will give us a better way to study early events in migraine development. Since stress is a migraine trigger reported by up to 79% of patients, we hypothesized that stressing the nestin/hRAMP1 mice could trigger light aversion. We have preliminary data demonstrating that acute stress preferentially induces light aversion in the nestin/hRAMP1 mice. We have previously found that anxiety-related behaviors in these mice are similar to control littermates and the differential stress-induced light aversion is apparently not due to the hypothalamic-pituitary-adrenal axis because corticosterone levels were similar in both transgenics and controls. Instead, a potential mechanism that is supported by new preliminary data is activation of mast cells. Mast cells contain a host of vasoactive and neuroactive substances that are known to be released by corticotrophin releasing hormone (CRH) following acute stress. We found that chemically induced mast cell degranulation preferentially induced light aversion in the nestin/hRAMP1 model. The overall objective of this project is to uncover the mechanism of stress-induced light aversion. The proposed research will specifically evaluate the involvement of CGRP, CRH, and mast cells in light aversive behavior. Aim 1 will address the role of CGRP and CRH in stress-induced behavior. This will be accomplished using a pharmacological approach with antagonists. The light/dark behavioral assay will be our main measure, with time spent in light as the primary parameter of interest. Aim 2 will focus on the role of mast cells in light aversion. Mast cells will be directly manipulated using the mast cell secretagogue Compound 48/80 as well as the stabilizing agent sodium cromoglycate. In addition to measuring light-aversion behavior following mast cell manipulations, neuronal activity patterns following stress and other treatments will be directly assessed using c-Fos staining. The major impact of this proposal will be characterizing a physiologically relevant animal model of migraine, which should allow for preclinical testing of new anti-migraine treatments. Additionally, it will provide some insight into the mechanism of how stress precipitates migraine. Overall, this project will assess the first evidence of a physiological trigger of a migraine symptom in an animal model. PUBLIC HEALTH RELEVANCE: Migraine is a painful headache disorder experienced by over 10% of Americans. In addition to headache pain, many people experience other symptoms during a migraine, including increased sensitivity to light and sounds. Since bright lights can cause pain during a migraine, we use mice to study the disorder by measuring how much time they spend in the dark when given a choice between light and dark sides of a box. We plan to learn more about how stress can trigger migraines.